In the 1920’s Warburg was characterizing the in vitro growth of rat hepatocarcinoma cells and observed that even in the presence of sufficient oxygen, tumor cells utilized an excess of glucose for conversion of lactate in the cytosol. Warburg attributed this to a dysfunctional mitochondria and a potential etiology of cancer origins. Under normoxic conditions in non-malignant cells glucose is transformed into pyruvate in the mitochondria and undergoes oxidative phosphorylation through the TCA cycle yielding 36 molecules of ATP per molecule of glucose. Rather, what Warburg observed was tumor cells undergoing aerobic glycolysis whereby converting a large amount of glucose to lactate in the cytosol for a limited ATP production (2 molecules of ATP per molecule of glucose) and an increased macromolecule production. Macromolecule production shuttles glucose-6-phosphate into the pentose phosphate pathway (PPP) for NADPH exchange allowing ribose-5-phosphate to increase nucleotide synthesis. This is essential for tumor cells to proliferate at a high rate.
More than 80 years ago, a German biochemist, named Otto Warburg made an observation that cancer cells exhibit an increased rate of glycolysis even in the presence of oxygen (13). By examining how Louis Pasteur’s observations regarding fermentation of glucose to ethanol might apply to mammalian tissues, Warburg discovered that unlike most normal tissues, cancer cells tend to convert glucose into lactate even in the presence of sufficient oxygen to support mitochondrial oxidative phosphorylation (14). Warburg hypothesized that cancer, or malignant growth, are caused by the fact that tumor cells mainly generate energy (ATP) through a non-oxidative breakdown of glucose. This differs from normal tissue, where the cells mainly generate energy (ATP) through oxidative breakdown of pyruvate (15). Pyruvate is an end product of glycolysis, and is oxidized within the mitochondria. Therefore, according to Warburg, the driving force behind the malignancy of cancer cells should be interpreted as deriving from a lowering of mitochondrial respiration. Warburg demonstrated that in the time it takes for a noncancerous cell to utilize one molecule of glucose to produce 36mols of ATP, the cancer cell (in a hypoxic environment) utilizes 13 molecules of glucose and only produces 26mols of ATP (15). This inefficiency of ATP production is a potential area of weakness that can be exploited through the use of glucose restricting dietary intervention and/or pharmacological intervention.